: Chromogranin A is a highly acidic protein found in the secretory granules of all endocrine cells and many neurons. Several biological activities have been reported for CGA and its peptides. An amino-terminal fragment of CGA inhibits vasoconstriction caused by K+ and norepinephrine and also inhibits secretion from parathyroid cells and lung endocrine tumor cells. A calf aortic smooth muscle cell line and bovine parathyroid cells bind the amino-terminal fragment of CGA with high affinity. CGA cDNA has been expressed in bacterial and mammalian cells and libraries of sequence-specific and monoclonal antibodies that can be used to study CGA and its product peptides have been developed by the applicant. Aim 1 is to define the structural and conformational changes in CGA which accompany changes in pH, Ca++ and catecholamine levels. The hypothesis to be tested is that pH, Ca++ and catecholamine levels shape CGA into the configuration required to generate biologically active peptides by exposing a specific subset of paired basic residues to the surface of the molecule. Aim 2 is to define the processing of CGA. Metabolic labeling experiments will be used to determine whether production of the amino terminal fragment of CGA formed by processing at the first two paired basic sites is limited to a few cell types or is cell-type dependent and therefore under the influence of all or only a few endocrine regulatory pathways. Specific inhibitors of intracellular processing and site specific antibodies will be used to determine the cellular localization of processing and probable processing enzymes involved. In vitro experiments with recombinant CGA will be used to determine how ligands that produce major conformational changes affect the exposure of processing sites which produce the amino-terminal fragments. Aim 3 is to analyze CGA[1-40](vasostatin)-receptor interactions and Aim 4 is to clone the vasostatin receptor.